Diacylglycerol kinase θ couples farnesoid X receptor-dependent bile acid signalling to Akt activation and glucose homoeostasis in hepatocytes

Cai, Kai; Sewer, Marion B.

doi:10.1042/bj20130609

Cited by 22 publications

(14 citation statements)

References 74 publications

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“…Therefore, our current results encourage us to identify and develop specifi c inhibitors/activators against every DGK isozyme that can be effective regulators and drugs against a wide variety of physiological events and diseases ( 4 ). For example, DGK ␣ : cancer cell growth ( 9,10,37,40 ), angiogenesis ( 41 ), T-cell proliferation ( 45 ), and T-cell anergy ( 12, 13 ); DGK ␤ : bipolar disorder ( 46, 47 ); DGK ␥ : actin reorganization ( 19 ), allergy ( 48 ), and insulin secretion ( 49 ); DGK ␦ : epidermal growth factor receptor signaling ( 50 ) and type 2 diabetes ( 51, 52 ); DGK : epidermal growth factor receptor signaling ( 53 ), lung cancer ( 54 ), bipolar disorder ( 55,56 ), unipolar depression ( 56 ), and attention-defi cit/hyperactivity disorder ( 56 ); DGK : hypospadias ( 57 ); DGK : seizure susceptibility/ long-term potentiation ( 58 ) and Huntington's disease ( 59 ); DGK : cell growth ( 60 ), T-cell receptor response ( 61 ), and brain ischemia ( 62 ); DGK : Ras signaling ( 63 ); and DGK : Parkinson's disease ( 64 ) and bile acid signaling ( 65 ).…”

Section: Discussionmentioning

confidence: 99%

A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response

Liu

Kunii

Sakuma

et al. 2016

Journal of Lipid Research

104

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Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid ( 1-6 ). To date, 10 mammalian DGK isozymes ( ␣ , ␤ , ␥ , ␦ , , , , , , and ) have been identifi ed. These DGK isozymes are divided into fi ve groups (type I-V) according to their structural features ( 1-6 ). Type I DGK isozymes (DGKs ␣ , ␤ , and ␥ ) commonly contain tandem repeats of two EFhand motif domains and are classifi ed as members of the EF-hand family of Ca 2+ binding proteins. In addition to the Ca 2+ binding EF-hand motifs, all type I DGK isozymes contain an N-terminal recoverin homology domain, two cysteine-rich C1 domains, and the C-terminal catalytic region ( 1-6 ).DGK ␣ ( 7, 8 ) is highly expressed in hepatocellular carcinoma and melanoma cells ( 9, 10 ). DGK ␣ expression is involved in hepatocellular carcinoma progression and is a Abstract Diacylglycerol kinase (DGK) consists of 10 isozymes. The ␣ -isozyme enhances the proliferation of cancer cells. However, DGK ␣ facilitates the nonresponsive state of immunity known as T-cell anergy; therefore, DGK ␣ enhances malignant traits and suppresses immune surveillance. The aim of this study was to identify a novel small molecule that selectively and potently inhibits DGK ␣ activity. We screened a library containing 9,600 chemical compounds using a newly established high-throughput DGK assay. Abbreviations: Con A, concanavalin A; CU-3, 5-[(2E)-3-(2-furyl) prop-2-enylidene]-3-[(phenylsulfonyl)amino]2-thioxo-1,3-thiazolidin-4-one; DG, diacylglycerol; DGK, diacylglycerol kinase; HTS, high-through put screening; IL-2, interleukin-2; PA, phosphatidic acid; PS, phosphatidylserine ; R59022, 6-(2-{4-[(4-fluorophenyl)phenylmethylene]1-piperidinyl}ethyl)-7-methyl-5 H -thiazolo-(3,2-a )pyrimidin-5-one; R59949, 3-(2-{4-[bis-(4-fl uorophenyl)methylene]1-piperidinyl}ethyl)-2,3-dihydro-2-thioxo-4(1 H )quinazolinone. This work was supported by Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. This work was also supported by MEXT/JSPS KAKENHI Grant Numbers 22370047 [Grant-in-Aid for Scientifi c Research (B)], 23116505 (Grant-in-Aid for Scientifi c Research on Innovative Areas), 25116704 (Grant-in-Aid for Scientifi c Research on Innovative Areas), 26291017 [Grant-in-Aid for Scientifi c Research (B)], and 15K14470 (Grant

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Section: Discussionmentioning

confidence: 99%

A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response

Liu

Kunii

Sakuma

et al. 2016

Journal of Lipid Research

104

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“…Gene Expression-Treatment of hepatocytes with CDCA stimulates Akt activity via mechanisms involving increased production of mitochondrial reactive oxygen species (32) and increased production of phosphatidic acid, a cellular metabolite that promotes Akt phosphorylation (33). These observations led us to investigate whether Akt plays a role in mediating the stimulatory effect of CDCA on FGF21 and ATF4 expression.…”

Section: Akt and Phosphorylated Eif2␣ Mediate The Stimulatory Effect mentioning

confidence: 99%

Glucagon and Insulin Cooperatively Stimulate Fibroblast Growth Factor 21 Gene Transcription by Increasing the Expression of Activating Transcription Factor 4

Alonge

Meares

Hillgartner

2017

Journal of Biological Chemistry

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Edited by John M. DenuPrevious studies have shown that glucagon cooperatively interacts with insulin to stimulate hepatic FGF21 gene expression. Here we investigated the mechanism by which glucagon and insulin increased FGF21 gene transcription in primary hepatocyte cultures. Transfection analyses demonstrated that glucagon plus insulin induction of FGF21 transcription was conferred by two activating transcription factor 4 (ATF4) binding sites in the FGF21 gene. Glucagon plus insulin stimulated a 5-fold increase in ATF4 protein abundance, and knockdown of ATF4 expression suppressed the ability of glucagon plus insulin to increase FGF21 expression. In hepatocytes incubated in the presence of insulin, treatment with a PKA-selective agonist mimicked the ability of glucagon to stimulate ATF4 and FGF21 expression. Inhibition of PKA, PI3K, Akt, and mammalian target of rapamycin complex 1 (mTORC1) suppressed the ability of glucagon plus insulin to stimulate ATF4 and FGF21 expression. Additional analyses demonstrated that chenodeoxycholic acid (CDCA) induced a 6-fold increase in ATF4 expression and that knockdown of ATF4 expression suppressed the ability of CDCA to increase FGF21 gene expression. CDCA increased the phosphorylation of eIF2␣, and inhibition of eIF2␣ signaling activity suppressed CDCA regulation of ATF4 and FGF21 expression. These results demonstrate that glucagon plus insulin increases FGF21 transcription by stimulating ATF4 expression and that activation of cAMP/PKA and PI3K/Akt/mTORC1 mediates the effect of glucagon plus insulin on ATF4 expression. These results also demonstrate that CDCA regulation of FGF21 transcription is mediated at least partially by an eIF2␣-dependent increase in ATF4 expression.FGF21 is an atypical member of the fibroblast growth factor family that lacks the ability to bind to heparin sulfate proteoglycans, allowing it to escape the extracellular matrix and function in an endocrine manner (1-3). Studies investigating the biological action of FGF21 have shown that starvation and other nutritional stresses (e.g. dietary protein restriction, consumption of a high-fat, low-carbohydrate ketogenic diet, and consumption of a high-fat obesogenic diet) stimulate an increase in the expression and secretion of FGF21 by the liver, the predominant site of FGF21 production in the body (4 -10). FGF21 signals through FGF receptor 1c (FGFR1c) linked to the co-receptor ␤-klotho to increase food intake, energy expenditure, gluconeogenesis, and insulin sensitivity and inhibit growth and female fertility in response to nutritional stress (1-6, 11).Several signaling pathways have been identified that mediate the effects of nutritional stress on FGF21 expression. One such pathway involves the activation of the nuclear receptor peroxisome proliferator-activated receptor ␣ (PPAR␣).2 A PPAR␣ response element (PPRE) has been identified in the 5Ј-flanking region of the murine and human FGF21 genes (8, 12). Ablation of the PPAR␣ gene suppresses the ability of starvation and ketogenic diet consumption to incr...

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“…Renga et al found that the FXR-KLF11 (Kruppel-like factor 11) pathway plays an important role in regulating insulin secretion induced by blood glucose [29]. Cai et al found that FXR can inhibit the mRNA expression levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase by increasing the expression of diacylglycerol kinase [30]. Transgenic mice fed high-fat Fig.…”

Section: Discussionmentioning

confidence: 99%

Knockout of farnesoid X receptor aggravates process of diabetic cardiomyopathy

Qiang

Tao²,

Zhou³

et al. 2020

Diabetes Research and Clinical Practice

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Previous studies have shown that FXR is involved in glycolipid metabolism, tissue inflammation and regeneration in organs such as the liver, intestines and kidneys. Although FXR has been reported in cardiac tissue, its function in diabetic cardiomyopathy has not been reported. Here, we successfully constructed a diabetic mouse model of FXR À/À and evaluated the effects of FXR knockout on cardiac function in mice by measuring various indicators. We demonstrated that blood glucose levels in diabetic mice are significantly elevated in the case of FXR knockout. Our findings from cardiac ultrasound and tissue HE staining supported that FXR knockout aggravates diabetic cardiomyopathy. Masson staining of myocardial tissue and quantitative detection of a-SMA by qPCR suggest that FXR knockout exacerbates cardiac fibrosis in diabetic cardiomyopathy. Combined with the results of Oil Red staining and quantitative detection of triglycerides in fresh tissue blocks, we hypothesized that FXR knockout aggravates diabetes-induced cardiac lipid accumulation. Altogether our results revealed a role of the FXR in the diabetic cardiomyopathy, suggesting a possible novel target for the treatment of diabetic cardiomyopathy.

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Diacylglycerol kinase θ couples farnesoid X receptor-dependent bile acid signalling to Akt activation and glucose homoeostasis in hepatocytes

Cited by 22 publications

References 74 publications

A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response

A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response

Glucagon and Insulin Cooperatively Stimulate Fibroblast Growth Factor 21 Gene Transcription by Increasing the Expression of Activating Transcription Factor 4

Knockout of farnesoid X receptor aggravates process of diabetic cardiomyopathy

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